Assessment of developmental toxicity of antiretroviral drugs using a rat whole embryo culture system

Background: Previous guidelines for HIV-infected pregnant women have recomm ended zidovudine (ZDV) monotherapy during the second and third trimesters o f pregnancy to prevent fetal HIV infection. New guidelines suggest that wom en should continue or be offered combination antiretroviral therapy (includ ing protease inhibitors) during pregnancy. Nevertheless, little animal or h uman toxicity data underlie these recommendations. Methods: We used an in vitro rat whole embryo culture system to assess the embryo toxicity of various nucleoside analogues, namely, ZDV, dideoxyinosin e (ddl), and 2',3'-dideoxycytidine (ddC), and the HIV-1 protease inhibitor, indinavir, both alone and in combination. Results: Although human fetal concentrations of these compounds are unknown , no gross abnormalities were detected after incubation with these agents, either alone or in combination at concentrations that would be expected to be achievable in human maternal serum (1-50 mu M). ZDV in combination with ddC at >100 mu M, resulted in severe growth retardation and morphologic abn ormalities not seen with either agent singly. Conclusions: We conclude that the combination of ZDV/ddC results in severe concentration-dependent embryo toxicity. No growth retardation or gross mor phologic abnormalities were found for any of the agents, either singly or i n combination, at clinically relevant concentrations. Teratology 62:108-114 , 2000. (C) 2000 Wiley-Liss, Inc.